Michigan Hepatotoxicity Clinical Research Network

描述(由申请人提供)： 由于大量处方药因肝毒性而被撤回或未能获得监管部门的批准，人们越来越意识到药物性肝损伤(DILL)的重要性。此外，DILL已被确定为美国急性肝功能衰竭的主要原因。然而，药物、毒素和辅助药物引起的肝损伤的发生率和危险因素仍不清楚，因为它们的性质不可预测，临床表现多种多样，而且缺乏诊断测试。异常的宿主免疫反应、母体药物的代谢激活和代谢产物的解毒作用与DILL的发病机制有关，但大多数病例涉及的分子机制尚不清楚。大多数DILL临床研究都是涉及少量患者和个别药物的非对照、回顾性病例系列研究。这项建议的主要目的是开发标准化的工具和方法来识别和表征药物、毒素和补充药物所致肝损伤的病例。将开发和验证简单、可重复使用的因果关系评估工具，以提供更准确的案例定义。这项建议的次要目标是建立一个肝毒性临床研究网络，该网络将前瞻性地纳入大量药物、毒素和补充药物引起的肝损伤病例，以及接受可疑药物但未出现毒性的病例对照。一项前瞻性病例对照研究设计将有助于确定DILL的潜在临床、免疫学和遗传危险因素。临床数据、血液、尿液、DNA和肝组织样本的收集将有助于后续研究药物、毒素和辅助药物所致肝损伤的分子发病机制，并可能有助于识别高危个体。

DESCRIPTION (provided by applicant): An increasing awareness of the importance of drug induced liver injury (DILl) has come from the large number of prescription drugs either being withdrawn or failing to gain regulatory approval due to hepatotoxicity. In addition, DILl has been identified as the leading cause of acute liver failure in the United States. However, the incidence and risk factors for drug, toxin, and complementary medication induced liver injury remain ill defined due to their unpredictable nature, varying clinical manifestations, and lack of diagnostic tests. Aberrant host immune responses, metabolic activation of the parent drug, and altered metabolite detoxification have been implicated in the pathogenesis of DILl but the molecular mechanisms involved in most cases remains unknown. The majority of DILl clinical studies have been uncontrolled, retrospective case-series involving small numbers of patients and individual agents. The primary aim of this proposal is to develop standardized instruments and methods to identify and characterize cases of drug, toxin, and complementary medication induced liver injury. Simple, reproducible causality assessment instruments will be developed and validated to provide more accurate case definitions. The secondary aim of this proposal is to develop a hepatotoxicity clinical research network that will prospectively enroll a large number of drug, toxin, and complementary medication induced liver injury cases as well as case controls that received the suspect drug but did not develop toxicity. A prospective case-control study design will help identify potential clinical, immunological, and genetic risk factors for DILl. Collection of clinical data, blood, urine, DNA, and liver tissue samples will allow for subsequent studies of the molecular pathogenesis of drug, toxin, and complementary medication induced liver injury and potentially help identify high risk individuals.